JPH0115501B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel pyridine derivative, a method for producing the same, and its pharmaceutical application. The novel compound group according to the present invention has the formula (): [Here, the group B is substituted at the 2, 3 or 4 position of the pyridine, n is 2, 3 or 4, and R ¹ is a linear or branched saturated alkyl having 1 to 10 carbon atoms.] or an alicyclic group (including cycloalkyl and cycloalkyl-alkyl), R ² and R ³ are C 1 -C 6 straight-chain or branched alkyl groups; or an alicyclic group, or R ² and R ³ may form a 5- to 7-membered heterocycle together with the nitrogen atom to which they are bonded; 2 heteroatoms and may be substituted with one or more substituents, especially one or more alkyl groups. The compounds of formula [] can form soluble salts with organic or inorganic acids. The compound of the present invention can be produced by either of the two methods shown in the following reaction formula. Pyridine acetonitrile (1) in the presence of acetic acid and piperidine as an aldehyde or ketone R ⁴ COR ⁵
(R ⁴ =H or alkyl, R ⁵ =alkyl or cycloalkyl) to obtain the ethylenenic nitrile compound (2). This is reduced, especially catalytically reduced, to obtain the saturated nitrile (3). Formula this: [In the formula, X represents a halogen] Compound (4) is obtained by reacting with a compound represented by the following and alkylating it, and hydrolyzing the nitrile group to an amide to obtain a compound of formula (). By appropriately selecting the groups R ⁴ and R ⁵ of the aldehyde or ketone used in the production of compound (2), linear,
Compounds with cyclic or branched saturated groups R ¹ can be obtained. Pyridine acetonitrile (1) is first converted to the formula: [In the formula, X represents a halogen] Alkylation is performed by reacting with a compound represented by the following formula to obtain a compound (5). This is then alkylated with a compound represented by R ¹ EXAMPLES The method for producing the compound according to the present invention will be explained in detail with reference to Examples below, but this is not intended to limit the present invention in any way. Example 1 2-(2-diisopropylaminoethyl)-2-
(2-pyridyl)-4-methylpentanamide (CM7857) (

【formula】

[Formula] n=2) (a) 4-Methyl-2-(2-pyridyl)-2-pentenenitrile In a flask equipped with a water separator, 7 g of 2-pyridylacetonitrile and 12.8 g of isobutyl aldehyde
g, 0.9 ml of acetic acid, 0.18 ml of piperidine, and 250 ml of anhydrous benzene. The mixture is heated under reflux for 3 hours, after cooling the reaction mixture is washed with water, the organic phase is dried over sodium sulfate and evaporated to dryness.
Distillation of the residue gives a yellow liquid. Yield 9.9g, bp=89-92℃/1.4mmHg (b) 4-Methyl-2-(2-pyridyl)-pentanitrile 9g of the compound obtained above was dissolved in 96℃ ethanol 100℃.
ml of the solution is hydrogenated at room temperature and pressure in the presence of 3.8 g of 5% palladium on carbon. The reaction mixture is filtered and the liquid is evaporated to dryness to give 9 g of a yellow liquid. This is used as is in the next step. (c) 2-(2-diisopropylaminoethyl)-2
-(2-pyridyl)-4-methylpentanenitrile 9 g of the nitrile obtained above, 9.3 g of 1-chloro-2-diisopropylaminoethane and 2.2 g of sodium amide dispersed in 150 ml of dry toluene
The mixture was heated to reflux for 2 hours. The reaction mixture is washed with water, the organic phase is dried over sodium sulfate and evaporated to dryness, yielding 15.1 g of an orange liquid.
This will be used as is in the next step. (d) CM7857 15.1g of the compound obtained above was dissolved in sulfuric acid (d=1.83)
Heat in 100ml for 1 hour. After cooling, pour this solution onto 600 g of ice while stirring. 40% to this mixture
Add a soda solution to make alkaline and extract with chloroform. The organic phase is dried over sodium sulfate and then evaporated to dryness. The residue was subjected to partition chromatography using an alumina column,
Elute with a mixture of pentane and ethyl acetate. 6.9 g of colorless solid are obtained. Recrystallize with isopropyl ether. Melting point = 107-108°C Reference example 2-(2-diisopropylaminoethyl)-2-
(2-pyridyl)-4-methyl-4-pentanamide (CM40348) (

【formula】

[Formula] n=2) (a) 4-diisopropylamino-2-(2-pyridyl)-butanenitrile 8 g of 2-pyridylacetonitrile, 8.81 g of 1-chloro-2-diisopropylaminoethane and benzyltriethylammonium chloride
Put 0.27g into the flask. Add 35ml of 50% soda while keeping the temperature below 35°C. This mixture is heated at 35°C for 5 hours. After returning to room temperature, dilute with water and extract with ether. The organic phase is dried over sodium sulfate and then evaporated to dryness. Distill the residue to obtain 9.36 g of yellow liquid. boiling point
132-134℃/0.6mmHg (b) 2-(2-diisopropylaminoethyl)-2
-(2-pyridyl)-4-methyl-4-bentenenitrile Sodium hydride (in oil)
Add 1.5 g (dispersed at a ratio of 55-60%) and 60 ml of dimethylformamide (DMF) under a nitrogen atmosphere. Add 7.35g of the above nitrile to this in DMF30
ml is added dropwise at room temperature. The mixture is stirred at room temperature for 30 minutes and 3 g of 2-methyl-3-chloropropene dissolved in 30 ml of DMF are added. The mixture is stirred at room temperature for 1 hour and the DMF is distilled off under reduced pressure. The residue is taken up in water and extracted with ether. The organic phase is dried over sodium sulfate and then evaporated to dryness, yielding 10.2 g of an orange liquid. This is used as it is in the next step. (c) CM40348 10.2 g of the compound obtained above, 36 g of potassium, 95%
Heat 150 ml of ethanol and 200 ml of water to reflux for 86 hours. The alcohol was distilled off and the mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulphate and evaporated to dryness. The residue is subjected to partition chromatography using an alumina column, eluting first with a mixture of pentane and ethyl acetate and then with ethyl acetate. 4.73 g of a white solid is obtained, which is recrystallized from hexane. Melting point 92−93
°C Example 2-21 By changing the starting material pyridylacetonitrile and other reactants and operating according to the method shown in the above Examples and Reference Examples, the first
The compounds listed in the table were obtained.

【table】

【table】

[Table] The pharmacological effects of the compound group according to the present invention, particularly antiarrhythmic effects, platelet aggregation inhibiting effects, and toxicity were investigated. (1) Antiarrhythmic effect Protocol The antiarrhythmic effect of these compounds was investigated using animal specimens with ventricular arrhythmia. The mongrel dog is anesthetized and a metal spire is attached to the coronal bed using retrograde catheterization. At the same time, a frequency modulating microtransmitter is fixed on the back of the animal and connected to the two precordial electrodes. When the animal was returned to the kennel, it showed signs of progressive thrombosis of the anterior ventricular artery. That is, regional and transmural infarction of the myocardium appears, which is the cause of abnormal repetitive electrical activity: tachycardia.
In this state, drugs were orally administered to the dogs, and the progress of rhythm arrhythmia was simultaneously tracked using a remote meter. By electrical methods, the pathological intersino-atrial systolic spike waves were permanently counted, and the properties and activity period of the test substance were determined. Results Results for various compounds are shown in Table 2. The activity of the compounds tested on ventricular tachycardia was expressed by whether they restored the sinoatrial rhythm or significantly improved the ratio (number of abnormal spikes)/(number of sinoatrial spikes). .

[Table] In humans, a single oral administration of 50 mg of CM7857 restored the sinoatrial rhythm. (2) Platelet aggregation inhibitory effect Protocol The antiaggregant effect was measured by in vitro and in vitro tests using Born's turbidity method. In vitro experiments were performed using platelet-rich human plasma. The test compound is dissolved in an isotonic solution of sodium chloride immediately before the experiment.
The compound is incubated in the presence of platelet-rich plasma for 5 minutes at 37° C. before adding the aggregating agent. In vitro experiments were performed on baboons that were given only water the day before testing. Test compound: 50mg/Kg
It was administered orally at a dose of Blood was collected before and 1, 2, 3, and 24 hours after administration of the test compound, and platelet aggregation was analyzed. The experimental results were expressed as % platelet aggregation inhibition relative to the control (100% aggregation). Results In vitro experiments performed on platelet-rich human plasma showed that CM7857 antagonized platelet aggregation induced by collagen. The concentration required to inhibit platelet aggregation by 50% is approximately 80 μm. In vitro experiments involved administering 50 mg/Kg of the compound to four baboons.
The test was conducted by administering the drug orally once. At this dose, ADP-induced platelet aggregation
30% blocked. In humans, a single oral administration of 50 mg/Kg of CM7857 cured diseases caused by platelet aggregation. Thus, it can be seen that the compound group according to the present invention has a strong effect on dysrhythmia and also has an antiplatelet aggregation effect. (3) Toxicity experiments When we investigated the toxicity of the compounds represented by formula (), we found that all of them had low enough toxicity to be used as medicines. The compound number produced in Example 1 is shown below.
The LD ₅₀ value of CM7857 is illustrated.

[Table] As a result of the above experiments, the compound represented by formula () can be used as a cardioprotective agent to treat disorders of ventricular rhythm caused by ischemia and disorders caused by platelet aggregation, and can be used in the treatment of human diseases. I found out that it can be done. These compounds can be made into dosage forms suitable for oral administration, such as tablets, capsules, and pills, and dosage forms suitable for parenteral administration, such as ampoules and vials. The daily dose required to exhibit antiplatelet aggregation effects and restore sinoatrial rhythm in humans is approximately 400 to 800 mg when administered orally. For intravenous administration, the dose is about 50 to about 150 mg. Examples of typical dosage forms are shown below. Tablet CM7857 0.200g Microcrystalline cellulose 0.140g Lactose 0.140g Magnesium stearate 0.020g 0.500g

Claims (1)

[Claims] 1 formula [In the formula, the substitution position on the pyridine ring may be any of the 2, 3, or 4 position, n is 2, 3, or 4, and R ¹ is a straight or branched chain having 1 to 10 carbon atoms. R ² and R ³ are straight-chain or branched alkyl groups having 1 to 6 carbon atoms, or an alicyclic group; Alternatively, R ² and R ³ may form a 5- to 7-membered heterocycle together with the nitrogen atom to which they are attached, and the heterocycle may include a second heteroatom. and optionally substituted with one or more substituents, in particular one or more alkyl groups] and salts thereof. 2 2-(2-diisopropylaminoethyl)-2
-(2-pyridine)-4-methylpentanamide,
or one of its inorganic acids or organic acid salts. 3 formula: A method for producing a compound or a salt thereof represented by (a) formula: Pyridylacetonitrile represented by the formula: R ⁴ COR ⁵ is reacted with an aldehyde or ketone, (b) the obtained nitrile compound having an ethylene group is reduced to a saturated nitrile compound, and (c) the obtained The formula for a saturated nitrile compound is: (d) Then, the nitrile group of the obtained compound is hydrolyzed to lead to the corresponding amide [wherein the substitution position on the pyridine ring is 2, 3 or 3] It may be at any of the 4-positions, n is 2, 3 or 4, and R ¹ is a linear or branched saturated alkyl group having 1 to 10 carbon atoms, or an alicyclic group. , R ² and R ³ are straight-chain or branched alkyl groups having 1 to 6 carbon atoms, or are alicyclic groups, or R ² and R ³ are bonded together. may form a 5- to 7-membered heterocycle, which may contain a second heteroatom and may contain one or more substituents, especially one or more substituents. It may be substituted with any of the above alkyl groups. R ⁴ represents hydrogen or an alkyl group, R ⁵ represents an alkyl group or a cycloalkyl group, and X represents a halogen group]. 4. The method according to item 3, wherein R ¹ is a saturated alkyl group or an alicyclic group. 5 Formula: A method for producing a compound or a salt thereof represented by the formula (a): Pyridylacetonitrile represented by the formula: (b) alkylate the obtained compound with a compound represented by the formula: R ¹ X; (c) then hydrolyze the nitrile group of the obtained compound to lead to the corresponding amide. [In the formula, the substitution position on the pyridine ring may be any of the 2, 3, or 4 position, n is 2, 3, or 4, and R ¹ is a carbon atom having 1 to 10 carbon atoms. Is it a straight-chain or branched saturated alkyl group or an alicyclic group, and R ² and R ³ are straight-chain or branched alkyl groups having 1 to 6 carbon atoms , or an alicyclic group, or R ² and R ³ may form a 5- to 7-membered heterocycle together with the nitrogen atom to which they are bonded, and the heterocycle may be a second heterocycle. atoms and may be substituted with one or more substituents, in particular one or more alkyl groups, X represents halogen]. 6 formula: [In the formula, the substitution position on the pyridine ring may be any of the 2, 3, or 4 position, n is 2, 3, or 4, and R ¹ is a straight or branched chain having 1 to 10 carbon atoms. R ² and R ³ are straight-chain or branched alkyl groups having 1 to 6 carbon atoms, or an alicyclic group; Alternatively, R ² and R ³ may form a 5- to 7-membered heterocycle together with the nitrogen atom to which they are attached, and the heterocycle may include a second heteroatom. and optionally substituted with one or more substituents, especially one or more alkyl groups] or a salt thereof. 7. The antiplatelet aggregation agent according to item 6, which is in a dosage form for oral or parenteral administration. 8. The antiplatelet aggregation agent according to item 7, wherein the daily oral dosage of the active ingredient is about 400 to about 800 mg. 9 Intravenous dosage of active ingredient from about 50 to about 150 mg
The antiplatelet aggregation agent according to item 7. 10 Formula: [In the formula, the substitution position on the pyridine ring may be any of the 2, 3, or 4 position, n is 2, 3, or 4, and R ¹ is a straight or branched chain having 1 to 10 carbon atoms. R ² and R ³ are straight-chain or branched alkyl groups having 1 to 6 carbon atoms, or an alicyclic group; Alternatively, R ² and R ³ may form a 5- to 7-membered heterocycle together with the nitrogen atom to which they are bonded, and the heterocycle may include a second heteroatom. and optionally substituted with one or more substituents, especially one or more alkyl groups] or a salt thereof. 11. The antiarrhythmic agent according to item 10, which is in a dosage form for oral or parenteral administration. 12. The antiarrhythmic agent according to item 11, wherein the daily oral dosage of the active ingredient is about 400 to about 800 mg. 13. Intravenous dosage of active ingredient from about 50 to about 150
The antiarrhythmic agent according to item 11, which is mg.